The present invention relates generally to the fields of medicine and biology. In particular, the present invention is directed towards compositions exhibiting ADP-ribosyltransferase activity which have prophylactic and/or therapeutic activity (e.g., in preventing cancer metastasis, preventing recurrence or reducing the incidence of cancers), as well as methods for the preparation and use thereof.
The use of surgery and radio- or chemotherapy to treat cancer involves the risk of serious side-effects and even death, yet frequently fails to produce substantive benefit. It is not surprising that these methods are rarely used to prevent cancer. It is clear there is a need for better methods to prevent or cure cancer and/or ameliorate the symptoms thereof in a patient.
Immune responses can effectively kill cells that display antigens that mark cells as harboring a pathogen. Vaccines containing such antigens can stimulate these desired responses and protect against disease with little risk. Coupling this experience with the hypothesis that malignant cells may also present a similar marker has led many investigators to search for vaccines that could prevent or cure various types of cancer [McCall, C. A., Wiemer, L., Baldwin, S., & Pearson, F. C. (1989) Bio/technology 7, 231-240; Rosenburg, S. A. (1992) J. Clin. Oncol. 10, 180-199; Prehn, R. T. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 4332-4333]. The successful development of such a vaccine would involve identifying preparations containing tumor-associated antigens, and learning how to prompt the immune system to properly and specifically kill cells displaying those antigens.
Some vaccines have been spectacularly successful at preventing infectious disease (e.g., smallpox); attempts to make other vaccines have, to date, failed (e.g., AIDS). At times, the lack of success may arise from a failure to elicit a proper response to an antigen, not the unavailability of a suitable antigen. These failures suggest that methods that control immune responses to antigens could greatly benefit the performance of vaccines designed to prevent, treat and/or cure infectious disease.
Similar issues face the development of cancer vaccines. For example, injecting irradiated tumor cells frequently fails to elicit an effective anti-tumor response. However, injecting irradiated tumor cells previously transfected with genes causing production of lymphokines (e.g., GM-CSF) [Dranoff, G., Jaffee, E., Lazenby, A., Golumbeck, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Pardoll, D., & Mulligan, R. C. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 3539-3543] can promote anti-tumor responses. Similar results have been obtained with tumor cells transfected to produce foreign major histocompatibility complexes [Plautz, G. E., Yang, Z. Y., Wu, B. Y., Gao, X., Huang, L., & Nabel, G. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 4645-4649], or adhesins, such as B7, normally found on the surface of antigen-presenting cells [Chen, L., Ashe, S., Brady, W. A., Hellstroem, I., Hellstroem, K. E., Ledbetter, J. A., McGowan, P., & Linsley, P. S. (1992) Cell 71, 1093-1102; Schwarz, R. H. (1992) Cell 71, 1068-1068; Baskar, S., Ostrand-Rosenburg, S., Nabavi, N., Nadler, L. M., Freeman, G. J., & Glimcher, L. H. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 5687-5690; Townsend, S. E., & Allison, J. P. (1993) Science. 259, 368-370]. Yet another approach has been to stimulate the immune system with bacteria or factors derived therefrom [McCall et al., 1989, supra].
Pertussis toxin is a protein released from the bacterium Bordetella pertussis. The administration of pertussis toxin along with a proper antigen markedly enhances antigen-specific autoimmune disease [Munoz, J. J. (1988) in Pathogenesis and Immunity in Pertussis (Wardlaw, A. C., & Parton, R., Eds.) Chapter 8, pp. 173-192, John Wiley & Sons Ltd., New York; Kamradt, T., Soloway, P. D., Perkins, D. L., & Gefter, M. L. (1991) J. Immunol. 147, 3296-3302] and antigen-specific delayed-type hypersensitivity reactions, but not antigen-independent inflammatory responses [Sewell, W. A., Munoz, J. J., & Vadas, M. A. (1983) J. Exp. Med. 157, 2087-2096; Sewell, W. A., Munoz, J. J., Scollay, R., & Vadas, M. A. (1984) J. Immunol. 133, 1716-1722]. There are reports [Likhite, V. V. (1983) U.S. Pat. No. 4,372,945; Minagawa, H., Kakamu, Y., Yoshida, H., Tomita, F., Oshima, H., & Mizuno, D. I. (1988) Jpn. J. Cancer Res. 79, 384-389; Minagawa, H., Kobayashi, H., Yoshida, H., Teranishi, M., Morikawa, A., Abe, S., Oshima, H., & Mizuno, D. I. (1990) Br. J. Cancer 62, 372-375] that crude preparations of B. pertussis can cause anti-tumor responses; the factor in these preparations causing this effect was not identified. Others have shown that lipopolysaccharides from B. pertussis can stimulate anti-tumor responses [Ohnishi, M., Kimura, S., Yamazaki, M., Abe, S., & Yamaguchi, H. (1994) Microbiol. Immunol. 38, 733-739; Ohnishi.M, Kimura, S., Yamazaki, M., Oshima, H., Mizuno, D.-I., Abe, S., & Yamaguchi, H. (1994) Br. J. Cancer 69, 1038-1042].
It is an object of the present invention to provide compositions and methods which do not suffer from the drawbacks attendant to the heretofore-available compositions and methods. In particular, it is an object of the present invention to provide compositions which increase the efficacy of other compositions and methods.